REVIEW ARTICLE published: 13 December 2012 doi: 10.3389/fgene.2012.00290 Mechanisms of arterial remodeling: lessons from genetic diseases

Bernard J. van Varik 1, Roger J. M. W. Rennenberg 1, Chris P.Reutelingsperger 2, Abraham A. Kroon 1, Peter W. de Leeuw 1 and Leon J. Schurgers 2*

1 Department of Internal Medicine, Medical Centre and Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands 2 Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands

Edited by: Vascular disease is still the leading cause of morbidity and mortality in the Western Olivier M. Vanakker, Ghent world, and the primary cause of myocardial infarction, stroke, and ischemia. The biology University Hospital, Belgium of vascular disease is complex and still poorly understood in terms of causes and Reviewed by: consequences. Vascular function is determined by structural and functional properties of Ying Xu, West Virginia University, USA the arterial vascular wall. Arterial stiffness, that is a pathological alteration of the vascular Wei Zhang, University of Michigan, wall, ultimately results in target-organ damage and increased mortality. Arterial remodeling USA is accelerated under conditions that adversely affect the balance between arterial function *Correspondence: and structure such as , , mellitus, chronic Leon J. Schurgers, Department of disease, inflammatory disease, lifestyle aspects (smoking), drugs ( antagonists), Biochemistry, Cardiovascular Research Institute Maastricht, and genetic abnormalities [e.g., pseudoxanthoma elasticum (PXE), Marfan’s disease]. The Maastricht University, aim of this review is to provide an overview of the complex mechanisms and different Universiteitssingel 50, PO Box 616, factors that underlie arterial remodeling, learning from single defect diseases like 6200 MD Maastricht, Netherlands. PXE, and PXE-like, Marfan’s disease and Keutel syndrome in vascular remodeling. e-mail: l.schurgers@ maastrichtuniversity.nl Keywords: arterial remodeling, calcification, genetic disease, vitamin K, vitamin K-antagonists

INTRODUCTION cardiovascular diseases such as hypertension, diabetes mellitus, Arterial remodeling refers to the myriad of structural and and chronic kidney disease as well as in normal vascular aging. functional changes of the vascular wall that occur in response to disease, injury, or aging. Although arterial remodeling can GENERAL FEATURES OF ARTERIAL REMODELING be regarded as a mechanism that naturally occurs with aging, Arterial remodeling is thought to reflect adaptation of the ves- early arterial remodeling is associated with significant hemo- sel wall to mechanical and hemodynamic stimuli (Nichols and dynamic changes and cardiovascular morbidity and mortality. O’Rourke, 2005). Arterial remodeling is characterized by alter- Arterial remodeling is set into motion by a variety of complex ations in the structure and function of the vascular wall and pathophysiological mechanisms that are closely interrelated, and can be divided into atherosclerosis and arteriosclerosis. Whereas that influence both the cellular and non-cellular components of atherosclerosis is characterized by a focal inflammatory process the vascular wall. Mechanisms involved in arterial remodeling in the intima initiated by accumulation of lipids in plaques, arte- include fibrosis, hyperplasia of the arterial intima and media, riosclerosis is a more diffusely localized alteration of the medial changes in vascular collagen and elastin, endothelial dysfunction, arterial vascular wall (Libby, 2002). Arteriosclerosis is associ- and arterial calcification. Migration and proliferation of vascu- ated with aging and generalized cardiovascular, metabolic, or lar smooth muscle cells (VSMCs) contribute to thickening of the inflammatory disease. Macroscopically, different types of arte- arterial intima. Differentiation of VSMCs from their contractile rial remodeling can be distinguished, depending on the type to a secretory or osteogenic phenotype may lead to increased and localization of the vessel (Figure 1)(Mulvany et al., 1996). vascular tone, and promotes (ECM) cal- Arterial remodeling can be either inward or outward and can be cification. Additionally, alterations in the activity of vitamin hypertrophic (thickening of the vascular wall), eutrophic (con- K-dependent proteins may affect the progression of vascular stant wall thickness), or hypotrophic (thinning of the vascular remodeling, including the induction of calcification. Because of wall) (Mulvany et al., 1996). Changes observed in arteriosclerotic this complexity, it is difficult to study to what extent a sin- arterial remodeling are mainly seen in large central elastic arteries. gle mechanism contributes to arterial remodeling. Monogenetic They are characterized by increased vessel diameter and thickened diseases such as pseudoxanthoma elasticum (PXE), PXE-like syn- intimal and medial layers of the vascular wall (outward hyper- drome, Marfan’s syndrome or Keutel syndrome are characterized trophic remodeling) (O’Rourke and Hashimoto, 2007). On the by a clinical phenotype that is similar to that of arterial remod- other hand, remodeling of muscular peripheral vessels is more eling, but are caused by a specific defect that affects only one often inwardly eutrophic or hypertrophic, probably reflecting or several pathophysiological mechanisms of arterial remodeling. sustained vasoconstriction of vessels (Mulvany, 2008). Lessons learned from these relatively rare diseases may there- Thickening of the arterial wall is caused by intimal hyperplasia, fore ultimately provide insight in more common, multifactorial medial hypertrophy and hyperplasia of VSMCs, and deposition

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remodeling of vascular tissue (Blaha et al., 2009; Sekikawa et al., 2012). In addition to structural changes, endothelial function plays an important role in arterial remodeling. Blood flow and shear stress stimulate endothelial cells to produce nitric oxide (NO), which in turn influences contraction and relaxation of VSMCs. Endothelial function decreases with age and endothelial dysfunction is com- mon in many cardiovascular diseases. Moreover, in response to pathological conditions, such as altered shear stress or inflam- mation, endothelial cells produce cytokines and growth factors that influence the homeostasis of the vascular wall (Csiszar et al., 2009; Urschel et al., 2012). Endothelial cells produce transforming growth factor-beta (TGF-β) and bone morphogenetic proteins (BMPs) which stimulate VSMCs and vascular pericytes to pro- liferate, to differentiate and to deposit ECM matrix (discussed in more detail below) (Simionescu et al., 2005; Boström et al., 2011).

PATHOGENESIS OF ARTERIAL REMODELING Arterial remodeling is driven by numerous, highly regulated and FIGURE 1 | Types of vascular remodeling. Adapted from Mulvany et al. interrelated processes. Processes that are of particular importance (1996). Different types of arterial remodeling can be distinguished: as they are central in arterial remodeling include: (1) VSMC hypotrophic (left column), eutrophic (center column) and hypertrophic proliferation and differentiation, (2) degradation and fracture of (right column). In addition remodeling can be either inward or outward. Hypotrophic remodeling results in a relative thinner wall and a lower elastin fibers, and (3) calcification and deposition of ECM mate- wall-to-lumen ratio. Conversely hypertrophic remodeling is characterized by rial (Figure 2). Genetic diseases with a phenotype resembling thickening of the vascular wall due to cellular hyperplasia and/or vascular disease all affect one or several of these key processes hypertrophy or deposition of extracellular matrix material and results in andmaythusprovidemoreinsightinthemechanismsofvascular increased wall-to-lumen ratio. When the diameter of the vessel changes but disease (Figure 3). the wall-to-lumen ratio remains the same it is called eutrophic remodeling. All types of arterial remodeling can occur in cardiovascular disease, depending on the underlying pathophysiology (e.g., aneurysm or VASCULAR SMOOTH MUSCLE CELL PROLIFERATION AND hypertensive arterial stiffening) and arterial site (e.g., central elastic DIFFERENTIATION arteries vs. peripheral resistance arteries). VSMCs are key regulators of vascular tone and health and insight into their function is of utmost importance for our understanding of the causes of arterial remodeling. In normal arteries, VSMCs of ECM material including minerals (Virmani et al., 1991; Safar in the tunica media regulate vessel tone and diameter in order to et al., 1998; Schwartz et al., 2000). The normal composition maintain hemodynamic balance (Alexander and Owens, 2012). and lay-out of ECM of the vascular wall is disrupted in arterial To fulfill this regulatory function, VSMCs need to have a con- remodeling. In the media of the normal arterial wall, elastic fibers tractile phenotype. Contractile VSMCs are characterized by a are arranged in parallel, concentric, fenestrated layers, alternating number of phenotype-specific marker proteins such as smooth with layers of VSMCs anchored to the elastic fibers and structural muscle 22-alpha (SM22α), alpha-smooth muscle actin (αSMa), fibers by glycoproteins and integrins (Dingemans et al., 2000; and smoothelin (Iyemere et al., 2006; Eys et al., 2007). Although Nichols and O’Rourke, 2005). These structures, termed elastic the majority of VSMCs in the vascular wall display a contractile lamellae, enable the vessel to expand and buffer the systolic blood phenotype, studies have shown that a specific subset of medial pressure pulse, while simultaneously maintaining structural sta- VSMCs has the ability to differentiate into a synthetic phenotype bility. Elastic fibers provide passive elastic buffering, whereas which can be further subdivided into a migratory-proliferative VSMCs dynamically redistribute tensile stress across fibers due to phenotype, a secretory phenotype or an osteogenic phenotype their ability to contract and relax (Rachev and Hayashi, 1999). (Gerthoffer, 2007). Phenotypic flexibility of VSMCs is necessary With arterial remodeling the layered architecture of elastic lamel- to deal with the varying conditions of vascular tissue. Stress sig- lae is lost as they become progressively fragmented and fibrotic nals switch gene expression that will modulate VSMC phenotype (Farand et al., 2007). At higher levels of blood pressure, vessels to adapt. This process of differentiation is termed phenotype dilate which results in increased tensile stress on the vascular wall, switching and is considered to be a key mechanism in arterial in accordance with LaPlace’s Law of circumferential wall tension remodeling (Iyemere et al., 2006; Alexander and Owens, 2012). (Nichols and O’Rourke, 2005). Thickening of the arterial wall Phenotype switching occurs in response to vascular injury occurring with arterial remodeling reduces tensile stress. VSMCs or stress and is characterized by reduced expression of of adults do not synthesize new elastin but mainly non-elastic which are specific for contractile VSMCs and cellular morphol- collagen resulting in stiffening of the vascular wall (Greenwald, ogy (Alexander and Owens, 2012). Although the precise mech- 2007). Closely related to the degradation of ECM, the deposi- anisms are still not fully understood, many different stimuli tion of calcium minerals further contributes to stiffening and have been identified, some of which are summarized in Table 1

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FIGURE 2 | Pathophysiological mechanisms of arterial remodeling. calcification and collagen deposition lead to adaptation of the vascular Cross sectional schematic view of the arterial wall. (A) Normal wall. Abbreviations: TGF-β, transforming growth factor-beta; IL-1, situation. (B) Arterial remodeling. Arterial remodeling is characterized interleukin 1; MMP, matrix metalloproteinases; VSMC, vascular smooth by thickening of the wall. Elastic fiber degradation, extracellular matrix muscle cell.

FIGURE 3 | Pathophysiological pathways leading to arterial remodeling in genetic and cardiovascular disease. Abbreviations: PXE, pseudoxanthoma elasticum; MMP, matrix metalloproteinases; VSMC, vascular smooth muscle cell; GGCX, gamma glutamyl transferase.

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Table 1 | Stimuli for vascular smooth muscle phenotype switching. for atherosclerotic plaque stability. VSMCs and myofibroblasts in the fibrous cap provide stability to atherosclerotic plaques Inflammation if they deposit collagen. On the contrary, if a significant part Oxidative stress of these VSMCs display a proteolytic phenotype, degradation Hemodynamic shear stress of fibrous cap material may facilitate plaque rupture (Johnson, Mechanical stretch 2007). Therefore, the role of VSMCs in maintaining atheroscle- Advanced glycation end products (AGE) rotic plaque stability largely depends on VSMC phenotype, stress- Increased calcium-phosphate product ing out the importance to find therapeutic agents that are able to SYSTEMIC HORMONAL modify the VSMC phenotype (Orr et al., 2010). Angiotensin II (Ang II) Aldosterone Osteogenic VSMC phenotype PARACRINE STIMULI Under specific stimuli such as sustained high extracellular levels Transforming growth factor-β (TGF-β) of calcium and phosphate or in the absence of inhibitors of calci- Fibroblast growth factor (FGF) fication, VSMCs can differentiate into an osteogenic phenotype Endothelial growth factor (EGF) in which VSMCs acquire features usually observed in chon- Platelet derived growth factor (PDGF) drocytes and osteoblasts (Shanahan et al., 1994; Iyemere et al., Matrix metalloproteinases (MMP) 2006). Osteogenic VSMCs are characterized by down regulation of mineralization inhibitory proteins, upregulation of alkaline phosphatase and release of matrix vesicles (MVs) (Shanahan (Alexander and Owens, 2012). Migratory stimuli, for instance, et al., 2011). In vitro, culturing VSMCs with elevated phosphate alter the cytoskeleton of VSMCs. As a consequence, cell adhesion concentrations results in up-regulation of osteogenic markers molecules are detached from the ECM and surrounding vascular (Runx2, osterix, and alkaline phosphatase) and down-regulation cells. Lamellipodia protrude from the leading edge of the cell due of VSMC lineage markers (SMa actin, SM22a) (Shanahan et al., to actin polymerization, enabling it to move through the ECM 2011). Downstream, bone morphogenetic protein-2 (BMP-2) toward a chemotactic stimulus (Willis et al., 2004). This migra- induces an osteogenic differentiation of VSMCs. BMP-2 has tion contributes to intimal VSMC proliferation and hyperplasia, been shown to be expressed in human atherosclerotic lesions whichisanimportantcauseofarterialwallthickening. (Boström et al., 1993). The phenotypic switch of VSMCs to Synthetic VSMCs produce elastolytic enzymes (matrix met- - and osteoblast-like cells by BMP-2 is limited by cal- alloproteinases; MMPs), which facilitate migration by detaching cification inhibitory proteins such as matrix Gla-protein (MGP). cells from the basement membrane and ECM. Indeed, upregu- In MGP knock-out mice, the absence of MGP results in heavily lation of MMPs coincides with the migration of VSMCs (Willis calcified elastic fibers, and loss of VSMCs which are differenti- et al., 2004). A genetic disorder that is associated with VSMC ated into chondrocytic VSMCs (Luo et al., 1997). Additionally, phenotype switching is Marfan’s disease. It is characterized by MGP deficiency in VSMCs results in decreased smooth muscle abnormal synthesis and function of elastic fibers (Kielty, 2006). markers which is accompanied by an up-regulated expression Patients with Marfan’s disease suffer from abnormal growth, of the bone-specific transcription factor cbf1a/Runx2 and the skeletal disorders, ocular problems and increased tendency to osteogenic protein osteopontin (Speer et al., 2002). The ability of develop aneurysms. The gene defect underlying Marfan’s disease MGP to keep VSMCs in the contractile phenotype may be accom- is a of the fibrillin-1 (FBN-1) gene, which encodes the plished by binding BMP-2 (Wallin et al., 2000; Zebboudj et al., glycoprotein FBN-1. FBN-1 is essential for maintaining struc- 2003). tural stability of elastic fibers, as well as attaching VSMCs to the Tanimura and co-workers were the first to report an associa- elastic fibers (Bunton et al., 2001). Because of defective synthe- tion between small membrane encapsulated particles, MVs, and sis, elastic fibers are prone to early mechanical fragmentation vascular calcification (Tanimura et al., 1983). Vesicular structures and therefore disruption of elastic laminae. However, additional have been found in both intimal and medial layers and were likely studies on the pathophysiological mechanisms in Marfan’s dis- derived from VSMCs (Kim, 1976; Bennett et al., 1995; Hsu and ease showed that, preceding elastic fiber degradation, impaired Camacho, 1999). The release of vesicle bodies from VSMCs was binding of VSMCs-induced differentiation into a synthetic pro- first described as a rescue mechanism against calcium overload teolytic phenotype (Galis et al., 1994; Bunton et al., 2001; Galis trying to prevent apoptosis of VSMCs (Fleckenstein-Grün et al., and Khatri, 2002). The resulting production of MMPs dam- 1992). VSMC-derived MVs have been identified in human arter- ages the already weakened vascular wall (Pratt and Curci, 2010). ies in association with atherosclerosis and hypertension (Kim, These patho-mechanistic changes in Marfan’s disease help to 1976; Kockx et al., 1998). In vitro,MVfromVSMCsformthe understand underlying mechanisms leading to general vascular nidus for calcification (Shanahan et al., 1999). disease. Indeed, Goodall et al. showed that VSMCs from infe- rior mesenteric veins of patients with aortic aneurysms display DEGRADATION AND FRACTURE OF ELASTIN FIBERS increased MMP-2 production and an increased number of migra- Elastin tory VSMCs (Goodall et al., 2002). Bendeck et al. demonstrated Elastic fibers consist of polymers of tropoelastin cross-linked to that inhibition of MMP activity inhibited VSMC migration in fibrillin-rich microfibrils. In the vasculature, elastin is mainly rats (Bendeck et al., 1996). Moreover, VSMCs are important produced during the fetal and neonatal period by (secretory)

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VSMCs. Above we discussed the importance of elastin for syndrome (Ziereisen et al., 1993; Munroe et al., 1999; Vanakker maintaining arterial wall stability and VSMC homeostasis in et al., 2007; Rutsch et al., 2011). Keutel’s syndrome is caused by Marfan’s Disease. Additionally, elastin is also an important nidus amutationinthegeneencodingMGP,whichisconsideredtobe for calcification. This is illustrated in PXE disease and its accom- the most important inhibitor of vascular calcification. MGP is a panying clinical features. PXE is characterized by extensive calcifi- 14 kD protein which requires vitamin K-dependent carboxylation cation that mainly occurs along elastic fibers. Although cutaneous to become biologically active. Clinically, lessons learned from the manifestations are primarily of cosmetic concern, presence of mechanisms underlying Keutel’s disease can help understanding characteristic skin lesions signifies risk for development of vascu- vitamin K-antagonist-induced vascular calcifications (discussed lar calcification with considerable morbidity and occasional early below) (Rennenberg et al., 2010; Weijs et al., 2011; Schurgers et al., mortality (Uitto et al., 2010). 2012). Even in the absence of diseases which directly affect elastin In PXE, the underlying genetic defect is a loss-of-function structure and function, similar processes can be observed in mutation of the abcc6 gene. This gene encodes a transmembrane vascular aging and aortic stiffening (Smith et al., 2012). The ques- transporter protein (Multi Drug Resistant Protein 6; MDRP-6). tion remains, what causes disruption of elastic fibers associated The substrate of the MDRP-6 is not known, and the exact mech- with aging? Initially, it was hypothesized that elastin degrada- anisms by which this mutation leads to elastin calcification are tion was predominantly the result of material fatigue caused by not yet fully understood. Recent studies have pointed toward cal- cyclic stretching of elastic fibers with every heart beat (O’Rourke, cification being stimulated by phenotype switching of VSMCs, 1976; Nichols and O’Rourke, 2005). Diseases such as (systolic) oxidative stress, and interference with carboxylation of MGP hypertension would accelerate this process, since increased pulse (Pasquali-Ronchetti et al., 2006; Garcia-Fernandez et al., 2008; pressure (PP) exerts greater tensile stress on the vascular wall and Boraldi et al., 2009; Li et al., 2009b; Rutsch et al., 2011). Similarly, increased stretch on fibers. In support of this hypothesis, struc- in PXE-like syndrome a mutation in the γ-glutamylcarboxylase tural alterations in elastin have been demonstrated to be inversely (GGCX) gene causes elastic fiber calcification as is observed in associated with total number of heart beat cycles in vitro (Avolio vitamin K-antagonist-induced vascular calcification (Gheduzzi et al., 1998). However, there are no in vivo studies supporting et al., 2007; Vanakker et al., 2007; Rennenberg et al., 2010; Weijs mechanical fragmentation of elastin. et al., 2011; Schurgers et al., 2012).TheGGCXmutationis associated with increased bleeding tendency due to impairment CALCIFICATION AND DEPOSITION OF ECM MATERIAL of vitamin K-dependent coagulation factors (Vanakker et al., Both VSMC phenotype switching and ECM degradation result 2007; Li et al., 2009a). This has led to the concept that vitamin in enhanced and accelerated vascular calcification. Initially, vas- K-dependent proteins are of importance in inhibiting vascular cular calcification was regarded as passive mineral deposition. elastin calcification. The GGCX mutation results in decreased However, this view has been abandoned since overwhelming activity of MGP and subsequently an impaired inhibitory poten- evidence exists that vascular calcification actually is a highly reg- tial for calcification, similar to the situation in Keutel’s syndrome ulated process. Soft tissue calcification is thought to result from in which MGP is absent (Schurgers et al., 2008; Vanakker et al., an imbalance between calcification-promoting and -inhibiting 2010). In a similar manner, treatment with vitamin K-antagonists factors (Table 2). Calcification is the hallmark of patients with may also induce an increased tendency for calcification (Figure 2) genetic diseases like Keutel’s syndrome, PXE, and PXE-like (Price et al., 1998; Schurgers et al., 2007; Rennenberg et al., 2010; Chatrou et al., 2012). Since vitamin K-antagonists work by inhibiting the Vitamin K cycle and by reducing carboxylation of MGP, these findings confirm the important central role of MGP Table 2 | Calcification regulating factors. in the regulation of calcification. Therefore, it is highly probable FACTORS PROMOTING CALCIFICATION that in these diseases, MGP also plays an important regulatory Bone morphogenetic protein 2 (BMP-2) role in calcification (Shanahan et al., 1999; Schurgers et al., 2007). ↑ Calcium-phosphate product Tumor Necrosis Factor α (TNF-α) CLINICAL ASPECTS OF ARTERIAL REMODELING Interleukin 6 (IL-6) Since the normal function of vessels is to maintain adequate Receptor activator of nuclear factor κB (RANK) ligand (RANKL) perfusion of organs and tissues and to buffer oscillating blood Insulin-like growth factor I (IGF-I) pressures, arterial remodeling results in changes in this func- Insulin tion. At first, these are compensatory (i.e., reducing wall tension). ↑ Glucose However, in later stages these compensatory mechanisms become ↑ Parathyroid hormone detrimental and initiate a vicious cycle of pathophysiological Matrix metalloproteinases (MMP) aberrations. Elastin degradation Hydroxyapatite crystals ARTERIAL REMODELING, ARTERIAL STIFFNESS AND DAMAGING FACTORS INHIBITING CALCIFICATION HEMODYNAMICS Fetuin-A Fragmentation of the elastic lamina, hyperplasia and hypertro- (MGP) phy of VSMC, loss of contractility of VSMC, deposition of Osteoprotegerin (OPG) collagen, and arterial calcification lead to stiffening of arteries.

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Many studies have shown that arterial stiffness, which is clinically as on vascular function, and to contribute to the vicious cycle of measured as the carotid-femoral pulse wave velocity (cfPWV), is arterial remodeling. independently associated with cardiovascular risk and mortality High blood pressure pulsatility leads to increased mechanical (Laurent et al., 2001, 2012; Mitchell et al., 2010; Vlachopoulos vascular wall stress. With high central PP, the amplitude in which et al., 2010). In addition, arterial stiffness is independently asso- the arterial wall expands and contracts with each consecutive ciated with, and predictive of target organ damage of the heart, heartbeat is increased. This leads to higher stretch on elastic and kidneys, and brain (Laurent and Boutouyrie, 2005). Arterial stiff- collagen fibers in the arterial wall and this in turn may contribute ness reflects the degree of remodeling in large arteries and is to material fatigue, fracture, and degradation. Additionally, cyclic used as a parameter for cardiovascular risk stratification next to stretching of VSMC has been demonstrated to stimulate phe- traditional cardiovascular risk factors (Nurnberger et al., 2002). notype switching and arterial remodeling (Williams, 1998). The mechanism linking arterial stiffness to an adverse outcome is Secondly, pathological blood pressure pulsatility adversely affects thought to involve a pathological hemodynamic profile in large, endothelial function since structure and function of the endothe- central arteries such as the aorta (Mitchell, 2009). This patholog- lium are modulated by hemodynamic forces (Gimbrone and ical hemodynamic pattern consists of an increased systolic blood García-Cardeña, 2012). In hypertensive patients, a high pulse- pressure (SBP; i.e., systolic hypertension) and decreased diastolic pressure is associated with endothelial dysfunction, which can be blood pressure (DBP) resulting in an increased PP. The pressure measured as the vasodilator response to acetylcholine (Ceravolo waveform in the aorta is composed of a forward traveling wave et al., 2003). In the normal situation, a laminar blood flow pat- generated by contraction of the left ventricle of the heart, and a tern and cyclic shear stress maintain proper endothelial function backwards traveling wave generated by reflection from peripheral such as: NO-mediated regulation of vascular tone, maintain- arteries (Figure 4A). This reflected wave is generated at vascular ing a non-thrombotic and non-inflammatory state, preserving bifurcations and at sites where the elastic conduit arteries tran- ECM metabolism, and regulating vascular permeability (Vita sition into muscular resistance arteries (Mitchell, 2004). At this and Mitchell, 2003; Gimbrone and García-Cardeña, 2012). In site the difference in impedance of the vascular wall causes the arteries with remodeling, blood flow becomes increasingly oscil- forward traveling wave to be reflected. The shape of the aortic latory with peaked systolic flows as well as stasis and even flow pressure waveform is largely determined by timing and speed reversal during diastole (Domanski et al., 1999; Mitchell, 2004). with which the pulse wave propagates through the arteries. With The ensuing turbulent flow and locally altered shear stress pat- arterial stiffening the speed of both the forward and backward terns cause endothelial dysfunction, which is characterized by traveling wave is increased. Remodeling of arteries causes an impaired NO synthesis and upregulation of pro-inflammatory earlier wave reflection. As a result of different timing of both and pro-atherogenic factors, increased oxidative stress, as well as waves, the forward traveling wave and the reflected wave are sum- vasoconstriction (Keulenaer et al., 1998; Blackman et al., 2002; mated, leading to an augmented systolic peak and a relatively Gimbrone and García-Cardeña, 2012). In addition, altered flow low DBP (Figure 4B), generating a highly pulsatile flow in aorta and increased pressure pulsatility have been shown to activate the and branching arteries. It is this blood pressure pulsatility that is endothelium and induce production of osteogenic factors such as thought to have damaging effects on sensitive target organs as well BMP-2 and BMP-4 (Qiu and Tarbell, 2000; Sorescu et al., 2003;

FIGURE 4 | Hemodynamic changes in arterial stiffening. (A) Aortic blood waveform of a person with arterial stiffness. Due to increased pulse wave pressure waveform of a healthy, normotensive person. The forwards traveling velocity, the forward traveling wave and reflected wave are summated wave precedes the (backwards traveling) reflected wave. (B) Aortic pressure leading to augmented pulse pressure.

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Boström et al., 2011). Indeed, BMP-2 transgenic apoE−/− mice significant cardiovascular risk (Budoff et al., 2006). The impor- display increased calcification of atheromatous lesions, whereas tance of calcification with respect to cardiovascular outcome is MGP transgenic apoE−/− mice have less atherosclerotic miner- further stressed by the fact that rapid annual progression of the alization, suggesting a key role for MGP in suppressing BMP-2- calcium score is independently associated with outcome (Raggi induced vascular mineralization (Nakagawa et al., 2010; Yao et al., et al., 2004). For this reason, the calcification process may become 2010). an important therapeutic target. The challenge is that an interven- Arterial stiffness and endothelial function not only stimu- tion should be aimed at a modifiable factor in the pathophysio- late the development of atherosclerotic plaques but also further logical process. As can be learned from PXE, PXE-like syndrome promotes arterial media remodeling. In this way, arterial stiff- and Keutel’s syndrome, MGP and the vitamin K cycle are among ness may explain the interrelationship of arteriosclerosis and the most important known regulators of calcification and VSMC atherosclerosis. phenotype switching. As described above, MGP requires vita- Finally, the pathological hemodynamic patterns due to arte- min K mediated carboxylation to be biologically active. Therefore, rial stiffness lead to damage of susceptible organs such as kidneys, treatment with vitamin K would theoretically inhibit or possibly brain, and heart. It has been established that arterial stiffness and reverse arterial calcification and slow down the development of chronic kidney disease are closely interrelated (Safar et al., 2004). arterial stiffness. Indeed, our group demonstrated that calcifica- Patients with primary kidney disease have accelerated arterial tion could be reversed in rats that had extensive calcification due remodeling and calcification due to altered homeostasis of cal- to warfarin treatment, by subsequently administering vitamin K cium and phosphate, high degrees of inflammation and oxidative (Schurgers et al., 2007). In humans, the 3-year daily supplemen- stress, uremia, altered cholesterol metabolism, and an activated tation of 500 mcg vitamin K on top of a multi-vitamin resulted in renin-angiotensin system (RAS) (Safar et al., 2004). Conversely, hold on progression of vascular calcification (Shea et al., 2009)In increased arterial stiffness and pressure pulsatility induce renal the observational Rotterdam study, high dietary intake of vitamin damage (Verhave et al., 2005; Ford et al., 2010; Briet et al., 2011; K was associated with better cardiovascular outcome and reduced Chen et al., 2011). Blood pressure pulsatility has been put forward coronary artery calcification (Geleijnse et al., 2004; Gast et al., to be able to cause renal damage. Although kidneys are normally 2009). Also, in post-menopausal women, treatment with vita- protected against high blood pressure by an effective autoregula- min K resulted in improved markers of vascular stiffness (Braam tion, abnormal blood pressure pulsatility has been shown to blunt et al., 2003). Furthermore, a recent study by Westenfeld et al. the renal myogenic response (Bidani and Griffin, 2004; Bidani showed that vitamin K2 supplementation reduced plasma lev- et al., 2009; Hultström, 2012), exposing the vulnerable glomerular els of inactive, undercarboxylated MGP (Westenfeld et al., 2012). microcirculation to damaging pressure oscillations (Safar et al., Since vitamin K has no reported adverse side effects, it might be 2012). a promising treatment for calcification. Clinical trials investigat- ing the effects of vitamin K supplementation on calcification and arterial remodeling are currently in progress. CALCIFICATION AS CARDIOVASCULAR RISK FACTOR AND POSSIBLE THERAPEUTIC TARGET ARTERIAL REMODELING AS POTENTIAL THERAPEUTIC TARGET In PXE, PXE-like syndrome as well as in Keutel’s syndrome, In addition to calcification, other pathophysiological pathways of arterial calcification is an important feature of the clinical phe- arterial remodeling such as arterial stiffening, fibrosis, or elastin notype. Besides these, arterial calcification is also observed in degradation may also be potential candidates for intervention. more common disorders such as diabetes, hyperparathyroidism, However, finding suitable, modifiable candidates has proven to be and chronic kidney disease as well as in vascular aging. In addi- a challenge. Although most existing antihypertensive drugs may tion, vascular calcification may be induced by drugs that adversely reduce arterial stiffness to some extent, it is difficult to determine affect the regulatory balance between factors inducing or inhibit- whether this effect is mainly due to blood pressure reduction or ing calcification. For instance, chronic treatment with vitamin represents a true effect on ECM remodeling (Boutouyrie et al., K-antagonists (such as warfarin) is associated with peripheral 2011). Since the RAS plays an important pro-fibrotic role in arte- artery calcification (Rennenberg et al., 2010). Calcification occurs rial remodeling it has been suggested that beneficial effects of in both arteriosclerosis and atherosclerosis. Aortic medial calci- RAS antagonists are (partly) due to their anti-fibrotic action, fication has been demonstrated to contribute to arterial stiffness independent of their effects on blood pressure. Indeed, Tropeano in different populations (Odink et al., 2008; Cecelja et al., 2011; et al. showed that treatment with 8 mg perindopril was associ- Sekikawa et al., 2012). Moreover, the presence of aortic cal- ated with lower carotid stiffness independently of the effects on cification is predictive of coronary artery disease (Jang et al., blood pressure, whereas a dose of 4 mg did not have such an effect 2012). Calcification of coronary arteries predominantly reflects (Tropeano et al., 2006). Similar blood-pressure-independent de- atherosclerosis and can be measured and quantified by com- stiffening effects have been reported for selective aldosterone puted tomography (CT) using the calcium-score. The calcium antagonists such as eplerenone (White et al., 2003), supporting score (expressed as Agatston units) has been used as a sensitive possible effects of RAS system inhibition on ECM remodeling. tool for risk stratification and decision-making regarding coro- Especially in diabetes, advanced glycation end-products (AGE) nary revascularization and diagnostic . A negative contribute to arterial stiffness by creating cross-links between calcium score indicates that the presence of atherosclerotic plaque elastic and collagen fibers. Therefore, the AGE crosslink-breaker is very unlikely, whereas a high calcium score is associated with alagebrium has received attention as potential de-stiffening drug

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(Zieman et al., 2007). This α-Aminoguadine compound and calcification that are also involved in common cardiovas- improved aortic stiffness and improved peripheral arterial cular disease and aging. Lessons learned from PXE, PXE-like endothelial function in hypertensive patients, independently of syndrome and Keutel’s syndrome have given attention to the blood pressure (Kass et al., 2001; Zieman et al., 2007). However, major calcification regulatory protein MGP and has provided a further research is required to properly assess the effects and possible new target for intervention. In this way, the continued safety of this class of drugs. study of these relatively rare genetic diseases may ultimately pro- vide us with potential new targets for therapeutic intervention CONCLUSION AND FUTURE PERSPECTIVES above and beyond traditional cardiovascular risk management Studying genetic diseases such as PXE, PXE-like syndrome, and treatment of risk factors. Conceivably, since VSMC pheno- Keutel’s syndrome and Marfan’s disease increase our knowl- type switching has such an important regulatory role in arterial edge about pathophysiological mechanisms underlying arte- remodeling, specifically targeting the direction of VSMC pheno- rial remodeling (summarized in Figures 2 and 3). Single gene type switching may prove to be promising. Ultimately, these novel defects of these specific diseases affect major regulatory path- concepts learned from studying specific genetic diseases can be ways such as VSMC phenotype switching, matrix degradation, applied to general cardiovascular medicine.

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